Alpha-substituted aralkyl esters of amino carboxylic acids



Patented Mar. 18, 1947 ALPHA-SUBSTITUTED ARALKYL ns'rnns or AMlNO CARBOXYLIC acme Henry Martin, Franz Hafiiger, and Karl G'ttzi,

Basel, Switzerland, assignors to Geigy A. G., Basel, Switzerland the firm .l. R.

No Drawing. Application September 11, 1943, Se-

rial No. 502,032. In Switzerland September 23,

The spasmolytic efiect of the benzyl alcohol and its esters, for instance of benzyl acetate and benzyl benzoate, is known (Macht, J. Pharmacol. Exp. Therapeuticsl), 197 (1917)). In View of the supposition that the capability ofeasy saponification of the esters would provoke a strong spasmolyse, benzyl esters of high fatty acids have been synthesized which may more easily be split by lipase than the benzyl esters of aromatic acids (H. Shonle and P. Q. Row, J. Amer. Chem. Soc. 43, 361 (1921)). Mortimer Bye (Ind. Engng. Chem. 13, 217 (1921)) recommends the benzyl succinate because of its non-poisonousness.

C. Nielsen and J. Higgins (J. Lab. Clin. Med. '7,

5'79 (1922)) also are of the opinion that the benzyl eifect of the esters results from the hydrolytic production of benzyl alcohol. On intravenous injection of benzyl benzoate and cinnamic acidbenzyl ester, they have stated a stronger efficiency of the latter.

On the other hand, E. Snapper, Griinbaum and Sturkop (Biochem. Z. 155, 163 (1925)) are of the contrary opinion. They are of the opinion that the eiiiciency results from the unsplit molecule and recommend the use of the difiicultly splittable N-benzyl phthalamidic acid (Klin. Wschr. 4, I, 389, 1925) which is obtainable in the trade in form of suitable salts. An analogous compound is the N-benzylmalonamidic acid.

Moreover, the following compounds have been proposed: the cholic acid benzyl ester, the benzyl esters of high molecular fatty acids (J. Amer. Chem. Soc. 43, 361 (1921)) andthe citric acid benzyl ester.

All these compounds are characterized by a spasmolytic musculotropic efiiciency of the papaverine; a neurotropic, atropine-like efficacy is missed. The same is the case for comparable benzyl other compounds, among which for example the acetobromopyrocatechine benzyl ether has become known.

It has now been found that basic esters of aralkyl alcohols which are substituted in a-position by at least one hydrocarbon radical possess a manifest atropine-like efficiency. Like atropine the new compounds show a considerable aneifects of the atropine are diminished oralso completely missed. Such an efficacy could-not have .been foreseen, as heretofore such a neurotropiclike efiiciency has become known only for basic substituted esters and amides of hydroxy acid derivatives, such as for example of tropic acid,

4 Claims. (61. 260247) corresponding aryl "alkyl ketones. 55

amygdalic acid, atroglycerinic acid, benzilic acid, 0- and m-hydroxybenzoic' acid or corresponding derivatives of benzoic acid, phenyl acetic acid and hydrogenation products thereof.

Beside the atropine-like efiect the newbasic esters of aesubstituted aralkyl alcohols develop also a manifest papaverine-like efiiciency and show still strong anesthetic and partly also manifest bactericidal properties. The corresponding quaternary compounds have a similar behaviour.

The basic esters of a-substituted aralkyl alcohols may be prepared according to Various methods. Thus, for" example, reactive esters of a-substituted benzyl alcohols, .e. g. the halides, can be interacted with salts of aliphatic amino acids disubstituted at the nitrogen atom or ordinary, e. g. aliphatic amino acid esters may be esterified by means of a-substituted benzyl alcohols. Moreover, it is also possible to cause metal compounds of a-substituted benzyl alcohols to react with basic substituted reactive aliphatic acids.

A further possibility of production consists in that a-substituted aralkyl alcohols are esterified with carboxylic acids which, instead of the amino group required according to the definition, possess a substituent being directl or indirectly replaceable by the amino group, such as for example the hydroxy group or halogen, and in that the disubstituted amino group is subsequently introduced. For this purpose it is advantageous to cause a-substituted aralkyl alcohols or salts thereof to react with aliphatic, acylated hydroxy acid halides or aliphatic halogen carboXylic acid halides in presence or absence of diluents, to replace the hydroxyl groups possibly present in the resulting compounds by hagolen and finally introducing the amino group.

Of course, instead of introducing directly the disubstituted amino group, it is also possible to effect the reaction in an indirect manner by'introducing primary or secondary amino groups, which for instance also can intermediarily be substituted by acy] radicals, and then subsequentlyproducing the desired N-substitution' in the usual manner.

As car-substituted aralkyl alcohols are to'be understood secondary and tertiary alcohols such as for instance may be obtained by substitution of the CHz-group of the benzyl alcohol. These substituents may for' example be of aliphatic,

araliphati'c, hydroaromatic or aromatic nature. Secondary ct-substituted benzyl alcohols can for instance be produced by catalytic reduction of the Secondary alcohols may also be recovered ac matic nuclei which may be condensed with each other.

By addition of alkyl halides, alkylene halides,

aryl sulfonic acid esters, dialkyl sulfates, aralkyl halides and so on, there are obtained in the usual manner quaternary ammonium compounds from the a-substituted basic aralkyl esters.

The new compounds may be used as therapeutics.

In order to fully understand the present invention, the same may now be illustrated by the following examples without being limited thereto, the parts being by weight, unless otherwise stated.

Example 1 A mixture of 12 parts of the silver salt of fl-diethylamin'o propionic acid and 10 parts of u-bromo-n-butyl benzene in 100 parts of absolute alcohol is heated for 6 hours under reflux, then the alcohol is removed in vacuo and the residue dissolved in diluted hydrochloric acid. After filtration, the solution is extracted with ether, the aqueous layer then filtered and, while cooling with ice, made alkaline by means of potassium carbonate. The free base is then extracted from this solution by means of ether, the ethereal solution washed with concentrated potassium carbonate solution, dried and evaporated. The final product distils at 12 mm. pressure at 170-1'7l C.

Example 2 diluted sodium carbonate solution, then dried and evaporated. The residue, the fl-bromopropionic acid-(n-propyl-p-methyl phenyl carbine-l -ester, boils at a pressure of 0.2 mm, at 11'7-l22 C. 18 parts of this bromide are treated with 20 parts of diethylamine while cooling and then heated under reflux for 2 hours at '70-80 C. After the addition of water and diluted hydrochloric acid until the solution has been made acid to Congo, the whole is shaken out with ether. Then the acid solution is made alkaline in the cold by means of potassium carbonate and the free base is finally extracted with ether. B. P. 0.1 mm 121-128 (3.; yield 13 parts.

' The carbinol is obtained by interaction of ptoluyl aldehyde with a n-propyl magnesium bromide solution in absolute ether, B. P. 12 mm- 1l0-116 0.

Example 3 By causing 22.1 parts of d-bromopropionic acid chloride to react with a solution of 23 parts of n- "propyl-3i4-dimethylphenyl carbinol and 11 parts boils at 127-129 0., at a pressure of 0.1 mm. 6 parts of this bromide and 4 parts of diethylamine are heated together for 2 hours at 60-'70 C. The base is obtained by treating the mixture with diluted acid, etherising and precipitating from the aqueous solution. It boils at -128 C. at 0.05 mm. pressure; the yield amounts to 4 parts.

The above p bromopropionic acid ester can also be interacted with ammonia or ethylamin and subsequently be ethylated, for instance with diethyl sulfate; thus it is also possible to alkylate the product up to the quaternary stage.

Example 4 17.5 parts of B-bromopropionic acid chloride are added dropwise at 5l0 C. and under cooling to a mixture of 20 parts of n-propyl-a-naphthyl carbinol and 8 parts of absolute pyridine in 100 parts of absolute ether. After heating for 1 hour under reflux water is added and the mixture is etherised. The ether solution is then washed with a cold sodium carbonate solution and evaporated, the residue being e-bromopropionic acid- (n-prcpyl-a-naphthyl carbine-) -ester, B. P. 0.1 mm. -162 C.

9 parts of this bromide are treated, while cooling, with 10 parts of diethylamine and then heated for 2 hours on the water-bath. The reaction product is dissolved in water and diluted acid, shaken out with ether and the base freed from the acid solution by means of a cold potassium carbonate solution. It distils at-167-1'71 C. at 0.1 mm. pressure.

Example 5 17.1 parts of e-bromopropionic acid chloride are allowed to drop at 510 0. into a solution of 18A parts of n-propyl-p-chloropheny1 carbinol and 16 parts of absolute pyridine in 100 parts of absolute ether and subsequently heated for 1 hour under reflux. From the reaction product the c-bromo-propionic acid-(n-propyl-p-chlorophenyl carbine-)-ester is isolated by the addition of water and by washing the ethereal solution with a diluted cold sodium carbonate solution. B. P. 0.1mm. 1 8131 C. 9 parts of this bromide and 6 parts of diethylamine are heated for 2 hours to 60-70 C. The base is obtained by treating the mixture with diluted hydrochloric acid, shaking with ether and saturating the aqueous solution by means of a cold potassium carbonate solution. B. P. 0.1 mm. 121-l24 C.

When using dimethyl--, dipropyl-, dibutylamine and so on, very similar final products are obtained.

Example 6 While stirring and cooling to 5-l0 C., 8.5 parts of c-bromopropionic acid chloride are allowed to drop into a solution of 8.2 parts of isobutyl phenyl carbinol and 7.9 parts of absolute pyridine in 100 parts of absolute ether and the interaction is completed by heating the mixture for one hour to 40 0. Water is then added, the ethereal solution is washed with a diluted sodium carbonate solution and finally evaporated. The residue is heated under reflux for 1 hour with about 8 parts of diethylamine. After completion of the reaction the mixture is treated with diluted acid, etherised and the base is freed from the aqueous cold solution by means of an alkali. The base which is obtained by extraction with ether boils at a pressure of 0.8 mm. at 138-140 C. Yield 6 parts.

Instead of diethylamine, dimethylamine may also be used; B. P. 1.2mm. 1 38-140 C.

from the latter the s-diethylamino propionic acid ester boiling at 132-136 C. at 0.1 mm. pressure are obtained.

Example 7 E Z 9 ramp e 17 arts of chloroacet 1 chloride are added 5 dropw i se and under cooling to -5 C. to a solum Surfing and 2 Wlth te tion of 24.6 parts of isobutyl phenyl carbinol and solutlFm ,9 parts OI BbmmODrOmPmC 301d 24 parts e absolute pyridine in 150 parts of chloridein 900 parts of absolute ether is allowed absolute ether, whereupon the whole is heated to drop Into. mlxture of 210 parts of 1 far 1 hour to 00 After the addition of Water 10 phenyl carbinol and 110 parts of absolute pyridine the ethereal solution is Washed by means of a m 900 pains P 9 ether- After havmg bicarbonate solution and evaporated. The isot h1s mlxture,fol hours on the Water butyl phenyl carbine chloroacetate boils at 145% bath, it 18 treated with water, then the ethereal at 12 mm pressure 5 parts of this solution is washed'with diluted bicarbonate solupound are heated for 1 hour to 70 -30 (3. with 5 15 i and evaporated filq parts of diethylainine. The base is then isolated acld-(cyclohexyl phenyl Gimme) ester therefrom in the usual manner. B. P. 12 mm. 162- at Pressure Tne ether 0 CJ yield 4 parts. residue is added dropwise and under cooling to C. to a solution of 150 parts of diethylamine Example 8 20 in 300 parts of absolute ether and then treated While cooling with ice 8 5 parts of I bromo for 3 hours on the water-bath. After having added much water, the mixture is acidified and g fl zfi i g 1 2; ggfg f f g ifi g i etherised. The aqueous solution is made alkaline in the cold by means of a oausti: lye and the g g 5 g; 0f gg i t base thus separated dissolved in an organic solfi %?gg i 3 3 3 g 22 i l f vent. The residue is stirred into 1 liter of 2-n hydrochloric acid; after a short time the hydroi gg g gg g zgfi gg a gs gggggfi ggg gg i chloride crystallises in form of fine needles meltsolution and evaporated. The ether residue is i g g g g g ofiwo g g kg igfi' ggg i j In is treated with diluted acid, etherised and the figgi gt g gfigggg gg$ 3353?$5 3 53; base make free in by means methy I JhenyI carbinol B. P. 0.1 mm. 131-135 (2. g g ii% i i gj gg g g ggig m ether 5 prepared according to Grignard from p-toluyl ea r inol is obtained by the interaction of aldehyde and cyclohexyl magnesium bromide equimolecular quantities of 3:4-dimethy1 benzalg 2: g i sfmle dehyde with an ethereal isobutyl magnesium 0 t Picom m 0 e Vanous b curd solution B P 9 1250434., C st1tuents, canbmol, acid and amine. The follow- 1 f nalo a en usm mg table shows a further summary of the differghenyl c arbnl 01 prepare? from ent constituents which can be combined together butylmagnesigm bromide and 3'4-dimethy1 benzin any Way, e designations having been chosen aldehyde B P 15mm -15 2 c. p-bromoaccording the fnowmg formula propionic acid (n -buty1 3:4-dimethylphenyl carbine-)-ester, B. P. 0.3 mm. 141-143 C., and Y Ar Y '3 Am 01 CH3 CH? -c1=horhom- N\ Cl CH:

CH; BrO 02135-- N czHi 0 3 CHz-CH=CH: omo-O- /C-H -N\ CH: CHPGH==CH7 CHa 05a 0112-052 \CHO CH-CHz-CHr- N o C CH3 A CHr-CH:

' Gom- N\ om CHr-CH:

Ar Y R I Am I clan-H,

(EEG-CH: CH: /CHa H300- 'NC2H5 01 02B,

GHQ-CH2 (C2 s)s CH2- SOaOaHsl-SOqCHz H:(3Hz

0 -NC H Cl C1115 CHFCH=CHQ N-CH5 Cl 03H;

Thus, by suitable selection and combination of I 02H components as set forth in the previous description, it is possible to produce, among others, the E30 0 CO CH? basic ester of the formula CH" (311: 01115 CH2 CzHa CH: OE being a colorless liquid of the B. P. 125-128 c.

Cg2 02m at 0.05 mm. pressure, possessing valuable thera- CH2 C peutic properties. I 4. A basic ester of the formula cal-om which is a colorless liquid of the B. P. 149-151 C. at 0.4 mm. pressure, and possesses valuable therapeutic properties. What We claim is:

l. The basic ester of the formula being a colorless liquid of the B. P. 151-156 C. at 0.03 mm. pressure, possessing valuable therapeutic properties.

2. The basic ester of the formula being a colorless liquid of the B. P. 148-151 C. at 0.4 mm. pressure, possessing valuable therapeutic properties.

3. The basic ester of the formula KARL GATZL REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Number Country Date 629,054 German Apr. 22, 1936 462,967 British Mar. 10, 1937 543,556 German Feb. 6, 1932 537,450 German Nov. 3, 1931 OTHER REFERENCES Well, Chemical Abstracts, vol. 18 (1924), p. 2325. 

